Novel higher aliphatic acid derivatives and compositions containing the same



United States Patent NOVEL HIGHER ALIPHATIC ACID DERIVATIVES AND COMPOSITIONS CONTAINING THE SAME No Drawing. Application March 15, 1955 Serial No. 494,565

14 Claims. (Cl. 260-404) The present invention relates to novel partial esters of N-higher aliphatic acyl amino polycarboxylic acid compounds, and to compositions containing the same.

Various condensation products of fatty substances with amino polycarboxylic acids have been suggested in the art, and certain .of 'such products have been proposed as wetting and dispersing agents and the like.

The novel compounds of the present invention are partial esters of N-higher aliphatic acyl amino polycarboxylic acid compounds. A preferred embodiment is directed specifically to thewater-soluble salts of mono-esters of N-higher fatty acyl aliphatic amino dicarboxylic acids. Such compounds by reason of the character and arrangement of substituent groups possess highly desirable antibacterial cha'racteristics permitting the formulation of eifective bacteriostatic and germicidal compositions.

Suitable examples of compounds within the scope of the present invention are the water-soluble salts of monoesters derived from N-higher fatty acyl aliphatic dicarboxylic acids and lower aliphatic alcohols such as monosodium mono-methyl N-lauroyl aspartate, mono-potassium monomethyl N-myristoyl aspartate, mono (tri-ethanolamine') monomethyl N-lauroyl aspartate, mono-sodium monoethyl N-lauroyl aspartate, mono-sodium monomethyl N-palmitoyl aspartate, mono-sodium monomethyl N-lauroyl glutamate, monopotassium monoethyl N- coconut fatty acyl glutamate, mono-sodium monoglyceryl N-lauroyl aspartate, mono-sodium monomethyl N-stearoyl aspartate, mono-sodium monomethyl N-oleyl glutamate, and the like. The compounds having a substantially saturated fatty acyl group of about 12 to 16 carbon atoms are preferred since these possess particularly beneficial properties.

Other novel salts are alkaline earth metal and heavy metal salts such as the corresponding calcium, magnesium, copper and zinc salts of the compounds referred to above, eg. calcium, magnesium, copper and zinc salts .of monomethyl N-lauroyl aspartate and glutamate. These salts are comparativelywater-insoluble however. The corresponding free acids of these. half esters may be suitably formed also such as monomethyl .or monoethyl N-lauroyl aspartate and glutamate.

These novel compounds may be prepared in any suitable inahner. It has been found; however, that they may be prepared in good yield and high purity by a two-stage process which comprises reacting the higher aliphatic acyl halide with the polycarboxylic amino acid in the presence .of an inert organic solvent to form thecorrespond- 'ingN-higher aliphatic acyl amino acid anhydride, and reacting said anhydride with antalcoholate to form the desired mixed ester-salt of the amino acid.

The aliphatic acid halide used as a reactant may be derived from the higher fatty acids and 'the like in known manner. These higher fatty. :acid halides have about 2,909,535 Patented Oct. 20, 1959.-

JCC

10 to 22 carbon atoms generally, and preferably about 12 to 16'carbon atoms. It is preferred to use the acid chloride through other halides such as the acid bromides may be employed also. Examples thereof are the acid chlorides and bromides of caproic, lauric, myn'stic, palmitic, stearic, oleic, lineolic acids and the like. These substances may be used alone or in any desired mixture thereof such as the higher fatty acid mixtures derived from various oils and fats, e.g. coconut, palm kernel, palm and cottonseed oils, tallow and their hydrogenated derivatives. 7

The amino acidto be condensed therewith is preferably a lower aliphatic amino polycarboxylic acid having a hydrogen atom directly attached to the nitrogen. The amino group may be unsubstituted such as in aspartic and glutamic acids or may have an inert substituent thereon such as a lower alkyl group, e.g. N-methyl aspartic acid. I

The acid halide and the amino acid may be employed in any suitable proportions to form the desired N-acyl amino acid anhydride. In general the reaction may be conducted using substantially stoichiometric ratios of the tworeactants. If desired, it is possible to use an excess of either reactant. It is preferred to use at least a stoichiometric amount of the amino compound in order that there may be a minimum of unreacted fatty acid material in the final reaction mixture.

The condensation should be conducted in the presence of an inert organic solvent as a reaction medium. Since the acidhalide is a liquid usually and the amino acid is a solid, the presence of a solvent permits the formation of a suspension of the reactants and'facilitates the reaction. The solvent medium should solubilize the resulting reaction product preferably which aids in the completion of the reaction. The solvent should be substantially neutral or inert to the formation of the anhydride. The

agitated during the condensation if desired. Any inert organic solvent may be used as desired, preferably the lower fatty acid esters of monohydric alcohols,-e.g. ethyl acetate, n-propyl acetate, isopropyl acetate, ethyl and methyl propionate. Other suitable oxygen-containing solvents are ethers such as N-propyl ether and dioxane. The presence in the reaction mixture of significant amounts of either strong alkali or acid is inadvisable since such conditions are not conducive to formation of the anhydride. The condensation reaction may be conducted at any suitable temperature below the decomposition temperatures of the ingredients. It is preferred to use elevated temperatures such as up to about the refluxing temperature of the reaction mixture, particularly at least about 50 C., in 'order to facilitate the reaction.

' The product of this reaction is the anhydride of the .N-acyl amino polycarboxylic acid and may be purified if desired in any suitable manner. The anhydride may be subjected to such purification techniques as washing, drying, solvent extraction or crystallization of, the product.

This acylated anhydride product may be reacted thereafter in any suitable manner to split the anhydride group and produce the desired partial ester derivatives. It has been found that such reaction may be conducted readily by admixing the anhydride with an alcoholate salt resulting in the obtention of the mixed ester-salt in a single unit reaction. The alcoholate which is used as a reactant may be derived from any suitable alcohol. It is preferred to use the alcoholates of lower aliphatic monohydric alcohols such as those having up to about 6 carbon atoms, e.g. methyl, ethyl, isopropyl, propyl and butyl alcohols. Other suitable aliphatic alcohols may be employed also which may be saturated or unsaturated, and primary, secondary or tertiary in character. The alcoholate salt may have any suitable cation, preferably alkali metal, such as sodium potassium, lithium, calcium, aluminum, copper and the like. Further examples of suitable alcoholates are sodium methylate, potassium ethylate, sodium isopropoxide and aluminum propoxide.

The anhydride and the alcoholate may be reacted in any suitable proportions in order to form the desired ester salt. In general, the reaction should be conducted using substantially stoichiometric proportions of the two reactants thereof, though it is possible to use an excess of either reactant if deired.

The reaction is conducted in a substantially anhydrous medium since the presence of substantial or significant amounts of water would hydrolyze the alcoholate and thereby inhibit the formation of the ester-salt directly. It is preferred to suspend or dissolve the reactants in an inert organic solvent medium as described for the preparation of the anhydride intermediate. This reaction may be conducted conveniently at room temperature but it is possible to use elevated temperatures also if desired.

The desired ester-salt may be recovered from the reaction mixture in high yield and purity. The solvent may be separated by distillation from the reaction mixture. The oxygenated solvents do not exhibit appreciable solubility for the estersalt and the product can be precipitated and separated by filtration. This reaction product may be further purified in any suitable manner including Washing, crystallization and the like.

When a particular salt of the partial ester has been obtained, such product may be reacted in any suitable manner to form other salts or the free acid of the partial esters. Thus an appropriate base such as calcium or magnesium hydroxide may be reacted with an alkali metal salt derivative, such as monosodium monomethyl N-lauroyl aspartate for example, to form the corresponding calcium or magnesium salt of the partial ester. The salt may be acidified by any suitable acidifying agent such as hydrochloric acid to form the free acid of the partial ester.

The novel compounds of the present invention exhibit unusually beneficial properties and therefore have utility in many fields of application, particularly in the formulation of antibacterial compositions.

Among the unusual properties is their antibacterial power on the oral flora (the complex mixture of microorganisms normally present in the mouth). These compounds exhibit a superior inhibiting effect on bacterial growth and the production of acid from fermentable carbohydrates by these microorganisms found in saliva. This superior inhibiting effect may be illustrated by the Snyder dilution test which is known in the art. As indicative of the specificity of action with respect to the chemical structure of these active ingredients, it has been found that the di-sodium N-lauroyl aspartate does not exhibit equivalent activity, but is inferior in antibacterial activity against the oral flora and in the inhibition of acid formation.

The substantially saturated mixed ester-salts of the N- higher fatty acyl derivatives, particularly those having about 10 to 16 carbon atoms in the fatty acyl group, exhibit also the unusual property of being adsorbed and released by proteinaceous material. By reason of such properties, these derivatives may have prolonged activity in such applications where adsorption upon proteins is possible. It has been found that the water-soluble salts of the indicated mono-esters exhibit a superior anti-baceterial power against oral bacterial even after such materials have been adsorbed upon protein. For

example, the monosodium monomethyl N-lauroyl aspartate shows a high degree of anti-bacterial activity after adsorption upon casein whereas the disodium N-lauroyl aspartate is inferior by comparison.

The novel compounds of the present invention exhibit antibacterial or bacteriostatic power against other microorganisms also. For example, such compounds have been found to inhibit the growth of Staphylococcus aureus bacteria.

In addition these novel compounds exhibit marked surface-active properties rendering them further useful in many other specific types of products also. The longchain fatty acyl group is primarily hydrophobic in character, whereas the free carboxyl or salt group of the partial ester is a more hydrophilic group. It is possible therefore to select the specific length of acyl chain, e.g. 10 to 18 carbons, and hydrophilic group, e.g. type of salt, such that the resulting compound may show affinities toward aqueous and/or fatty or oily matters. Accordingly, it is possible to produce compounds of desired surface activity to fit the requirements for a particular use or class of uses. They may be used in various applications as detergent, wetting, foaming and emulsifying agents and the like.

Various products in which these novel compounds may be utilized either for anti-bacterial effect or surface activity are cosmetic and detergent compositions and the like. Such preparations include ointments, lotions, skin creams, jellies, shampoos, shaving creams, detergent bars or cakes, cleansing and laundering compositions.

It is an embodiment of the present invention that these novel compounds may be utilized in preparations designed for application in the month. There may be prepared suitable tooth powders, toothpastes, liquid dentifrices, mouth washes or rinses, chewing gum, tablets, lozenges and the like. Any suitable amount of these novel compounds may be incorporated in the oral preparations. The specific amount will vary, naturally, depending upon the specific type of preparation and the specific effects desired but will generally be a minor amount, such as up to about 50% by weight. In the case of tooth powders and dental creams, these new ingredients will be up to about 10% and preferably up to about 5%- by weight of the finished formulation generally.

Any suitable practically water-insoluble polishing agent may be admixed with these novel compounds in the preparation of dentifrice compositions of the present invention. There is a relatively large number of such materials known in the art. Representative materials include, for example, calcium carbonate, dicalcium phosphate (anhydrous or hydrated), tricalcium phosphate, calcium pyrophophate, insoluble sodium metaphosphate, aluminum hydroxide, magnesium carbonate, calcium sulfate, bentonite, including suitable mixtures thereof.

In the preparation of tooth powders, it is usually sufficient to admix mechanically the various solid ingredients. In dental cream formulations, the liquids and solids should necessarily be proportioned to form a creamy mass of desired consistency which is extrudible from a collapsible tube. In general, the liquids in the dental cream will comprise chiefly water, glycerine, sorbitol or propylene glycol, including suitable mixtures thereof. It is usually advantageous to use a mixture of both water and a humectant or binder such as glycerine or sorbitol.

Other known materials may be incorporated in suitable amounts. A gelling agent such as the natural and synthetic gums and gum-like materials, e.g. Irish moss, gum tragacanth, sodium carboxymethylcellulose, starch, may be added to the dental cream and the like in small amounts. Furthermore, such materials as soluble saccharin, flavoring oils, coloring or whitening agents, preservatives, alcohol and the like may be used as desired in proper amount.

As indicated mouth washes or rinses and the like are also within the scope of the present invention. Such products are usually an effective amount of the active ingredient dissolved or dispersed in a flavored'liquid vehicle, preferably an aqueous alcoholic vehicle. Any suitable amount, such as up to five percent active ingredient may be used.

Other compositions will be formulated in known manner also.

The following examples are illustrative of the present invention and it will be understood that the invention is not limited thereto. All parts are by weight unless otherwise specified.

Example] 23.5 gms. of lauroyl chloride are added to 30 gms. of aspartic acid suspendedin 500 ml. of dry ethyl acetate and the mixture is refluxed for twelve hours. After the solution has cooled the solid material is removed by filtration. The filtrate is distilled under vacuum to remove the ethyl acetate solvent and the oily residue is crystallized from Skellysolve E (mixed octanes). The crystalline product is filtered, washed and dried and the yield is 9 gms. of N-lauroyl aspartic anhydride: Percent N: calc. 4.71; found 4.81.

The N-lauroyl aspartic anhydride (2 gms.) is dissolved in 10 ml. of dry acetone. A 5% solution of sodium methylate in methanol is added until the pH rose to 9.0. The solvent is removed from the reaction mixture under vacuum and the residue is dried .over P The product is the mono-sodium salt of monomethyl Nlauroyl aspartate. Percent N of half esterzcalc. 3.99, found 3.86.

The above ester-salt is acidified with sulphuric acid to a pH of about 2, extracted with ether, washed and dried. Upon recrystallization from hexane, there is recovered the monomethyl N-lauroyl aspartic acid, M.P. 92-94 C.

Example 11 Aspartic acid and palmitoyl chloride are reacted under the same conditions as in Example I resulting in the formation of N-palmitoyl aspartic anhydride as the intermediate, and in the recovery of mono-sodium salt of monomethyl N-palmitoyl aspartate as the final product.

Example III 30 gms. (.2 mole) of glutamic acid and 22 gms. (.1 mole) of lauroyl chloride are reacted in 100 ml. of dry ethyl acetate at the reflux temperature for 18 hours. The

hot reaction mixture is filtered and the ethyl acetate filtrate is cooled to room temperature. During cooling an initial crop of crystals is isolated which is lauric acid. The solvent is removed under vacuum from the filtrate and the residue is dissolved in Skellysolve C (heptane) and allowed to crystallize therefrom. The crystalline product is filtered and dried and is N-lauroyl glutamic anhydride.

.38 grams of the above anhydride is dissolved in dry acetone and 12.25 ml. of 0.1 N-sodium methoxide solution is added to the mixture. The solvent is removed from the reaction mixture under vacuum and the product is dried over P 0 and the product after drying over P 0 is the mono-sodium salt of monomethyl N-lauroyl glutamate.

The above ester-salt is treated as in Example I resulting in monomethyl N-lauroyl glutamic acid, MP. 114- 115 C.

Example I V Glutamic acid and myristoyl chloride are reacted under the same conditions as in Example III resulting in the formation of Nmyristoyl glutamic anhydride as the intermediate product, and in the recovery of monosodium salt I of monomethyl N-myristoyl glutamate as the final product.

Example V A satisfactory dental cream having superior antibac- "6 terial properties is prepared in the usual manner according to the following formulation:

Percent the balance consisting essentially ofsoluble. saccharin, flavor and preservatives.

In the above dental cream, the monsodium monomethyl N-lauroyl glutamate may be substituted for the aspartate compound with similarly satisfactory results.

Example VI A satisfactory tooth powder may be prepared similarly according to the following formulation:

Percent Sodium monomethyl N-lauroyl aspartate 3.0 Dicalcium phosphate dihydrate 94.2 Flavor 2.5 Soluble saccharin 0.3

Although the present invention has been described with reference to particular embodiments and examples, it will be apparent to those skilled in the. art that variations and modifications of this invention can be made and the equivalents can be substituted therefor without departing from the principles and true spirit of the invention.

Having thus described the invention, what is claimed is:

1. An alkali metal salt of a mono-ester of N-higher fatty acyl aspartic acid and a saturated lower aliphatic alcohol.

2.. An alkali metal salt of a mono-ester of N-higher fatty acyl glutamic acid and a saturated lower aliphatic alcohol.

3. Mono-sodium monomethyl N-lauroyl aspartate.

4. Mono-sodium monomethyl N-lauroyl glutamate.

5. A monoester of (a) a saturated lower aliphatic alcohol and (b) an amide selected from the group consisting of higher fatty acid amides of a saturated lower aliphatic monoamino dicarboxylic acid and its mono-carboxylate salts.

6. A water-soluble mono-carboxylate salt of a monoester of (a) a saturated lower aliphatic alcohol and (b) a higher fatty acid amide of a saturated lower aliphatic monoamino dicarboxylic acid.

7. A water-soluble mono-carboxylate salt of a monoester of (a) a saturated lower aliphatic monohydric alcohol and (b) a saturated higher fatty acid amide of a saturated lower aliphatic monoamino dicarboxylic acid, said fatty acyl group having about 10 to 16 carbon atoms.

8. A composition comprising a monoester of (a) a saturated lower aliphatic alcohol and (b) an amide selected from the group consisting of saturated higher fatty acid amides of a saturated lower aliphatic monoamino dicarboxylic acid and its monocarboxylate salts, and a carrier therefor.

9. An anti-bacterial composition which comprises a water-soluble mono-carboxylate salt of a monoester of (a) a saturated lower aliphatic alcohol and (b) a saturated higher fatty acid amide of a saturated lower aliphatic mono'amino dicarboxylic acid, said fatty acyl group having about 12 to 16 carbon atoms, and a carrier therefor.

10. An anti-bacterial composition in accordance with claim 9 wherein said carrier is a cream.

11. A process which comprises condensing a higher fatty acid halide with a saturated lower aliphatic monoamino dicarboxylic acid having a replaceable hydrogen atom in the amino group in the presence of an inert organic solvent to form the corresponding N-higher fatty acyl amino dicarboxylic acid anhydride, reacting said anhydride with a saturated lower aliphatic alcoholate salt '7 and forming a monoester of (a) said saturated lower aliphatic alcohol and (b) an amide selected from the group consisting of higher fatty acid amides of said saturated lower aliphatic monoamino dicarboxylic acid and its monocarboxylate salts.

"12. A process which comprises condensing a higher fatty acid halide with a saturated lower aliphatic monoamino 'dicarboxylic acid having a replaceable hydrogen atom in the amino group in the presence of the corresponding N-higher fatty acyl amino-dicarboxylic anhydride, reacting said anhydride with an alkali metal saturated lower aliphatic ialcoholate salt and forming an alkali metal carboxylate salt of a monoester of (a) a saturated lower aliphatic alcohol and (b) a higher fattyacid amide of said saturated lower aliphatic monoamino dicarboxylic acid.

13. A process in accordance with claim 12 wherein the amino acid is aspartic acid.

14. A process in accordance with claim 12 in which the amino acid is glutamic acid.

References Cited in the file of this patent UNITED STATES PATENTS 

1. AN ALKALI METAL SALT OF A MONO-ESTER OF N-HIGHER FATTY ACYL ASPARTIC ACID AND A SATURATED LOWER ALIPHATIC ALCOHOL.
 11. A PROCESS WHICH COMPRISES CONDENSING A HIGHER FATTY ACID HALIDE WITH A SATURATED LOWER ALIPHATIC MONOAMINO DICARBOXYLIC ACID HAVING A REPLACEABLE HYDROGEN ATOM IN THE AMINO GROUP IN THE PRESENCE OF AN INERT ORGANIC SOLVENT TO FORM THE CORRESPONDING N-HIGHER FATTY ACYL AMINO DICARBOXYLIC ACID ANHYDRIDE, REACTING SAID ANHYDRIDE WITH A SATURATED LOWER ALIPHATIC ALCOHOLATE SALT AND FORMING A MONOESTER OF (A) SAID SATURATED LOWER ALIPHATIC ALCOHOL AND (B) AN AMIDE SELECTED FROM THE GROUP CONSISTING OF HIGHER FATTY ACID AMIDES OF SAID SATURATED LOWER ALIPHATIC MONOAMINO DICARBOXYLIC ACID AND ITS MONOCARBOXYLATE SALTS. 